Peripheral neuropathies are major neurological complications of multiple chemotherapy drugs causing significant morbidity affecting quality of life and potentially altering life-saving chemotherapy regimens. Many chemotherapy drugs with diverse mechanisms of actions cause axonal degeneration and the underlying mechanisms that lead to distal axonal degeneration, a common feature of most peripheral neuropathies are poorly understood. Furthermore, currently there are no therapies aimed at preventing, reversing or slowing the progression of peripheral neuropathies that cause chronic neuropathic pain, sensory loss and weakness. In this grant we will approach this problem in two ways. In aim 1, we will examine the molecular mechanisms of distal axonal degeneration induced by paclitaxel as it relates to various pathways that have been linked to Wallerian degeneration. In aim 2, we will examine the molecular mechanisms of a novel neuroprotective compound, ethoxyquin. Recently, we have identified ethoxyquin as a novel neuroprotective compound that interferes with chaperone activity of heat shock protein 90 (hsp90) and prevents distal axonal degeneration induced by a variety of molecular insults, including paclitaxel. Completion of these studies will give us a better understanding of mechanisms of distal axonal degeneration in chemotherapy-induced peripheral neuropathy and help further explore a novel therapeutic target that can be taken to clinical studies in a timely manner.